Evaluating Effective Treatment Options and Strategies for Relapsed/Refractory Mantle Cell Lymphoma

Finding the right treatment for patients with mantle cell lymphoma (MCL) in the second-line setting can be difficult, as there currently is no standard of care. If a patient experiences a response from treatment, it may typically last between 5 to 10 years with lower overall response rates (ORR).

During a presentation at the National Comprehensive Cancer Network 2022 Annual Congress: Hematologic Malignancies, Tycel Phillips, MD, clinical associate professor at City of Hope National Medical Center in Durate, California spoke about finding the optimal treatment for patients with MCL.¹

Phillips reviewed treatment options such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), as well as options post-bruton tyrosine kinase (BTK) inhibitors. Additionally, he spoke about adverse event (AE) profiles observed with each treatment, and which patients would benefit the most from these options.

Second-Line Treatment Options

Ibrutinib

Phillips began by discussing a study (NCT01236391) that first showed the effectiveness of BTK inhibitors in MCL.² In this trial, patients were broken out into arms of either no prior treatment with bortezomib (Velcade; n = 63), prior treatment with bortezomib (n = 48), and all patients (n = 111). The ORR was 68%, 67%, and 68%; the complete response (CR) was 19%, 23%, and 21%; and the partial response (PR) was 49%, 44%, and 47% in those with no prior treatment, prior treatment, and all patients, respectively.

The median duration of response (DOR) was 15.8 months (95% CI, 5.6-not reached [NR]) in those with no prior treatment, NR in those with prior treatment, and 17.5 months (95% CI, 15.8-NR) in all patients. The median progression-free survival (PFS) was 7.4 months (95% CI, 5.3-19.2), 16.6 months (95% CI, 8.3-NR), and 13.9 months (95% CI, 7.0-NR) in those with no prior treatment, prior treatment, and all patients, respectively. Finally, the median overall survival (OS) was not reached across all 3 treatment arms.

A compilation study looked at multiple BTK inhibitor studies to determine when the best time to use these treatments.³ In those with 1 prior line of therapy, the median PFS was 33.6 months (95% CI, 19.4-42.1), and the median OS was NR. The median DOR was 4.5 years for patients who achieved a CR, and those with 1 prior line of therapy had 2 times longer DOR than those with more than 1 previous line. This study showed it’s best to use BTK inhibitors in earlier lines of therapy vs later.

Acalabrutinib

In a study assessing the ORR of acalabrutinib (NCT02213926), in the investigator-assessed group the ORR was 81% vs the independent review committee (IRC) of 80%.⁴ The CR was 40% vs 40%, and the PR was 41% vs 40% in the investigator-assessed and IRC groups, respectively.

Dose reductions occurred in 1.6% of patients, and 6.5% discontinued treatments because of AEs. Regarding AEs, atrial fibrillation was not observed, with the most common AEs being headaches (36%) and diarrhea (38%), of which were mostly grade 1 and 2. Hematologic AEs were mostly grade 1 and 2 and included bruising and petechiae. Additionally, there was 1 grade 3 gastrointestinal hemorrhage. Phillips noted that recent reports have raised concerns about the cardiac related AEs with this treatment, but that more time and study is needed with this new class to fully assess their AE outcomes.

Zanubrutinib

Phillips also spoke about zanubrutinib with a study again assessing ORR (NCT02343120).⁵ In the investigator-assessed group the ORR was 90.6% (95% CI, 75.0%-98.0%) vs 84.4% (95% CI, 67.2%-94.7%) in the IRC group. The CR was 31.3% vs 25.0% and the PR was 59.4% vs 59.4% between both groups, respectively. The median PFS was 21.1 months, and the DOR was 18.5 months.

AEs that were grade 3 or higher included major hemorrhage (9.4%), atrial fibrillation or flutter (3.1%), hypertension (3.1%), and infection (18.8%).

Of note, Phillips mentioned that there is no main difference between ibrutinib, acalabrutinib, and zanuburtinib efficacy-wise. The reason they are separated is based on their AE profiles differing.

Combination Therapies for MCL Treatment

Phillips first discussed the phase 2 PHILEMON study (NCT02460276) that looked at the combination of ibrutinib, lenalidomide (Revlimid), and rituximab (Rituxan) in relapsed or refractory patients.⁶

This study focused on patients who either had TP53 mutations in their disease or did not. The ORR was 76% (95% CI, 63%-86%) in all patients, 79% (95% CI, 64%-89%) in TP53 unmutated, and 73% (95% CI, 43%-90%) in TP53 mutated. The CR rate was 28% (95% CI, 42%-69%), 21% (95% CI, 40%-70%), and 64% (95% CI, 35%-85%), while PR was seen in 20% (95% CI, 11%-33%), 24% (95% CI, 13%-39%), and 9% (95% CI, 2%-38%) in all patients, patients with TP53 unmutated disease, and those with TP53 mutated disease, respectively. However, Phillips explained that this was not the right combination for patients with MCL in the second-line setting.

In the phase 3 SYMPATICO investigation (NCT03112174) of ibrutinib plus venetoclax (Venclexta) patients were evenly split between those without a PET scan and those with.⁷ Looking at response at 4 weeks there was none recorded for those who had a PET scan, but when looking at best response, the CR was 67% for those without a PET scan vs 71% for those with a PET scan. PR was 4% vs 0%. Phillips noted that certain patients in this trial had a TP53 mutation, and at follow-up, they relapsed quickly. However, this combination may still be effective in those without TP53 mutations.

When venetoclax was first analyzed in humans (NCT01328626), the PFS and OS determined it was an effective agent for the treatment in MCL.⁸ However, the study consisted of patients who were BTK-naive and may not be reflective of what is seen in the real-world setting, according to Phillips. He then deemed the question for clinicians to think about was how effective is venetoclax as a single agent or even in combination with rituximab post-exposure to a covalent BTK inhibitor

CAR T-Cell Therapies in MCL

In the phase 2 ZUMA-2 trial (NCT02601313) brexucabtagene autoleucel (brexi-cel; Tecartus) was analyzed in patients with MCL.⁹ The efficacy of this study was promising. After 12.3 months of follow-up, the median PFS and OS, and DOR had not been reached, but overall, 57% of patients and 78% who obtained a CR are still in remission. While he acknowledged longer follow up was needed for this therapy, results suggest a promising treatment for patients that fail BTK inhibitors.

Cytokine release syndrome (CRS) and neurotoxicity were observed in this population. Grade 3 or higher CRS occurred in 15% of patients, and the most common symptoms were pyrexia (91%), hypotension (51%0, and hypoxia (34%). Tocilizumab (Actemra) was given to 59% of patients and corticosteroids to 22% to help manage symptoms.

Grade 3 or higher neurologic AEs occurred in 31% of patients, with the most common symptoms being tremors (35%), encephalopathy (31%), and confusional state (21%). Patients were given either tocilizumab (26%) or corticosteroids (38%) to help mitigate symptoms, with the majority of patients having resolution of their symptoms. 

Bi-Specific Antibody Options

Additional treatments for MCL were discussed including glofitamab.¹⁰ A trial conducted found it produced a high response rate in patients with relapsed/refractory MCL. In the fixed dosing group of 1000 mg (n = 3), the complete metabolic response (CMR) was 67%, 71% in those receiving step-up dosing plus 1000 mg of glofitamab (n = 7), 64% CMR and 27% partial metabolic response (PMR) in those receiving step up dosing plus 2000 mg of glofitamab (n = 11), and 67% CMR and 14% PMR for all patients. In those receiving prior BTK inhibitor therapy, the CMR was 65% and the PMR was 18% compared with 75% for no prior therapy.

Pirtobrutinib was discussed with patients either being pre-treated with BTK inhibitors, or BTK-naïve.¹¹ The ORR was 51% (95% CI, 41%-61%) in those who were pretreated, with a CR of 25%, and a PR of 26%. In those who were BTK-naive, the ORR was 82% (95% CI, 48%-98%), with a CR of 18% and a PR of 64%. The median follow-up was 8.3 months for patients who responded, and 60% of responses are ongoing.

Phillips concluded that it may be difficult to treat patients with MCL who have previously received a BTK inhibitor, but efficacy was improved with the use of CAR T cells. Moving forward, there are other agents that show positive outcomes, but they are currently limited to clinical trials.

^References

^{1. Phillips T. Optimizing Treatment for Relapsed/Refractory Mantle Cell Lymphoma. Lecture presented at NCCN 2022 Annual congress: Hematologic Malignancies; October 14-15, 2022; New York City, NY.}

^{2. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516. doi:10.1056/NEJMoa1306220}

^{3. Rule S, Dreyling M, Goy A, et al. Median 3.5-Year Follow-up of Ibrutinib Treatment in Patients with Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis. Blood. 2017;130(suppl 1):151. doi:10.1182/blood.V130.Suppl_1.151.151}

^{4. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659-667. doi:10.1016/S0140-6736(17)33108-2}

^{5. Tam CS, Opat S, Simpson D, et al. Zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma. Blood Adv. 2021;5(12):2577-2585. doi:10.1182/bloodadvances.2020004074}

^{6. Jerkeman M, Eskelund CW, Hutchings M, et al. Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. Lancet Haematol. 2018;5(3):e109-e116. doi:10.1016/S2352-3026(18)30018-8}

^{7. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211-1223. doi:10.1056/NEJMoa1715519}

^{8. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma. J Clin Oncol. 2017;35(8):826-833. doi:10.1200/JCO.2016.70.4320}

^{9. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347}

^{10. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068. doi:10.1200/JCO.2013.54.8800}

^{11. Wang M, Shah NN, Alencar AJ, et al. Pirtobrutinib, a next generation, highly selective, non-covalent BTK inhibitor in previously treated mantle cell lymphoma: updated results from the phase 1/2 BRUIN study. Blood. 2021;138(suppl 1):381. doi:10.1182/blood-2021-149138}